Project Summary Depression is a critical medical challenge affecting the morbidity of millions of people living with HIV despite availability of effective antiretroviral therapy (ART). Subsets of patients with depressive disorders do not respond to traditional antidepressant treatments, potentially reflecting disease mechanisms not addressed with standard therapy. This multidisciplinary proposal seeks to understand the interactions between host factors and neurological function by identifying metabolic pathways altered in depression using novel high-throughput metabolite profiling coupled with neuroimaging and immunological studies. This K23 Mentored Clinical Scientist Research Career Development Award details a comprehensive five-year program for the candidate to acquire formal training and mentorship with specific expertise in advanced computational modeling, and immunity and host defense. In this K23 proposal, the candidate will carry out a neurological substudy within the framework of a randomized, double-blind, placebo controlled trial in participants with HIV infection. First, the candidate aims to study cerebral function by positron emission tomography (PET) imaging with 2- [18F]-fluorodeoxyglucose (FDG), a sensitive indicator of neural activity and will define relationships with immune cell markers and depression. Second, the candidate seeks to determine the influence of monocyte subsets and activated T-lymphocytes on depression in treated chronic HIV-infection. Third, by studying the blood metabolome from HIV-infected individuals with depression in cross-sectional analysis and validating findings in an independent longitudinal cohort, the candidate will learn how systemic byproducts of metabolic pathways may be used to identify people living with HIV who are ?at risk? for persistent depressive symptoms. During the course of the award, the candidate will explore systemic metabolic pathways influencing depression in HIV-infected adults on ART with the goal of identifying potential novel diagnostic and therapeutic targets. The candidate is a board-certified neurologist with prior doctoral training in molecular biology and neuroscience. In preparation for an independent research career, the candidate will complete training in bioinformatics for analyzing large-scale datasets, and immunology through coursework and analysis of clinical, biological and metabolite data derived from the neurological substudy and multiple existing cohorts with chronic HIV infection. The candidate?s training will be guided by established mentors in the field of HIV infection and an advisory committee of senior scientists with collective expertise in HIV-associated neuropathogenesis and metabolic disease, metabolomics, computational modeling, bioinformatics, biostatistics, and neuroimaging.